Preparation of cycloalkyl ethers



1 is directed to arec'es's of-preparing Patented May 8, 1951PiiEPARATION F oYoLoALkYL titres -to ElifLllly and"Comp-any,ln'dianapolis; -Ind.,

ahor iolatioii of Iiidiana Nb Drawing; 1 Aii iieati ii September 25;1947,

Serial No. 7765145 7 Claims. (Cl'.=260 -473) 'I'hi'sinventionrelatsto'cycloalkyl'ietherjsl and fourth'to onef'hali of an equivalent of borontriolpentyl fluoride or'sulfuric acid is added totlie solution.

"and cyclohe'xyl ethers ofp hydroxybenzbic aicid The mixture is heated,desirably with agitation, "andesters'thereof. until the cycloalkene hasreacted with the hy- .The cycloalkyl ethersj prpai'ed in a cBrda iice"f'droxylgfroup of th'e'p-hydroxybenzoyl compound with this inventionniay 'be re1tiresehteclby the and thereaction is complete. The desiredcycloformula 'alkyl ether formed during the reaction may then l beisolated and purified in any conVenientman- ROC00Rl A ner. Thus forexample} whenj'the solvent emy ployed is water-immiscible the cycloalkylether wherein R represents a cyclopentyl or cyclohexyl m y be "i lat dby washing the cooled reaction radical and *Rrrepresents hydrogeri dranesteriiyi ture with water toremove'the boron trifluoing radicalThe"compounds represehted-above "ride or sulfuric acid; evaporating theorganic solhaveutility as intermediates-'i'ir the" syiith'esi's' of Iphase'tvherein the cycloalkyl ether is dis- 'loca'l anestheticconipounds.

ed and purifying the cyoloalkyl ether which e d b yq q f ib p- "re ainsas a residue, When the product is a aratior-r of ethers requiresas oneorthe"-starting "eycl'oalkyl'ether of a benzoic acid est any materials'a'c'yclo'alkyl halide andcomprise reactreacted p' hydroxybenzoic acide'ster is readily reing the halide with a p-hydroxybenzoic acid estermij q th ffmfi t ct t aquepusflp 'in the-presence-ot an alkali'su'chassodium"mthzokali in which the hydroxy compoundis soluble.

oxide; While this method'maybe satis'iactory 'for whenthe product is anether of p-hydroxybenpr p h w r' lky h rs; it is'unsuitable zoic'acid,fractional crystallization from glacial f r pr p r n 'i r 'q n itie' 'qfycloalkyl eth'ers acetic acid readily yields the desired ether in puresince the cycloalkyl "halides are expensive andnot form.

readily available; and the-prolonged heatin' 're- 5 J In'my intention, imay useas a starting maquired to causethe reaction 'of' the cyclo'alkylterial either p -hydroxybenzoic acid or anester of halide results'in theformatior'i' ofun'desired, oinp hydrox yberiz oic acid. Many esters aresuitable 'p Y-D GUCtsW Ch uct yield of the "but because of their readyayailabilityl prefer to cycloalkyl ether andmake its isolation in pureuse the alkyl esters wherein the esterifying radiform tedious anddifficult. ell isan alkyl'radicalhaving from i to 6 carbon -An objectofthe present invention is to 'provide "atoms,iorexample amethyl, ethyl,propyl, butyl, aprocessofpreparing cyclopentyl and 'cyclo'hexyl aifiyl'or heg yl radical.

=ethers-ofbenzoic acid-and-esters thereof} in g'ojod Thfirfi unt' fcatalyst; employedlinthe reacyield. Another -object is to provide aprocess "tionisnot critical. For maximum yields; the

which-utilizes relatively-inexpensive and readily por rr tirifluqrige grcoricer trat ed sulfuricacid is available starting-materials"Otherbbje'cts" -wi1l used in an amount equivalent to aboutone fourthbecome apparent fromthedisclosure inadeherein. fto one half of theamount oi; benzoic acid orester In pursuance-of the above-andother-"objects, I used. smalle amounts unnecessarily prolonghave-discovered that the cycloalkyhethers repre- 'the'rea'ction, andlarger amounts tend to promote 'sentedby the-formula given abovefeadilymaybe A side reactions. 1 prepared by subjecting a mixture of acycl'oalk'ene, The temperatures at which the reaction may be i-.- e.-,cyclopentene' or cyclohexenej and" a "'p-'hycarried out nay be within arange of about 40 C.

droxybenzoyl compound; is a; "p hyd'r'oiybenaoic 125 C Ihe-preferredtemperature when acid or one of its esters;*"- to*-=the action fof aconcentrated sulfuric acid is employed, is about catalystmf a group"consisting of "boronftrir- 90 C. and When-boron trifiuoride isusedjaboutfluoride-and-coneentrated suliuricacid.- 'I'-he cat- C. When an inertsolyent is employed, it is alyst causes thebondensatiomof-th cyclpalkeheconvenient to choose a'solvent whose boiling point with thehydroxylgroup-of the p hydroxybefiioyl approximates the temperatureg'at whichthe'reaccompound;thusproducirigthe desired cycloallyl tion is to becarried out so that the refluxingof ether. V the reaction mixturemaintains both the desired The follow-ing is -'illustrative=' of-*- aheat regulation and agitation of the solution.

1 ifi iavefound th at' a eltalraner ii ,ejyclopenta'nol-or'cyclohexanol;may be used as astartdissolved ing n'at rir w mi pig is the catalyst. in a hon-reactive 6rg ai-'1ie= s elfiehtiahd abc iut "dhe "Thiac'id dehydratesthe"cycloalkanol' to yieldin :situthe cycloalkene which reacts with the 1p-hydroxybenzoyl compound andforms the cycloalkyl ether. When a cycloalkanol is used, .sufiicientsulfuric acid should be used to effect both dehydration and catalysis,and the temperature should :be high enough to cause distillation fromthe solution of the water formed by the dehydration of the cycloalkanol.

"The inert solvent which may be used in my invention is any solventwhich will not take part in the reaction. I have found that solventssuch :as benzene, toluene and saturated hydrocarbons lboiling aboveabout 40 C. are quite satisfactory. Numerous other solvents will readilybe apparent to one skilled in the art. If desired, one may dispense withthe presence of the inert solvent, particularly so if an excess of thecycloalkene is employed. However, such practice involves a loss ofvaluable reactant and hence isnot a preferred manner of carrying out myprocess.

Specific examples which further illustrate the process of my inventionare as follows:

Example 1 80 g. of ethyl .p-hydroxybenzoate and 81 g. of cyclohexene aredissolved in 500 ml. of benzene, :and 15 g. of BE; are added over aperiod of :minutes. A slight spontaneous temperature rise occurs. Heatis then applied and the solution while stirred is maintained at 50-54 C.for about one half hour. The solution is then cooled and washed withwater to remove the BF3. The benzene layer containing the cyclohexylether is washed with 150 ml. of per cent NaOI-I solution to removeunreacted ethyl-p-hydroxybem zoate, and is then washed with water toremove any alkali. The benzene is evaporated, leaving as a resdue ethylp-cyclohexyloxybenzoate which is sufiiciently ure for most purposes butwhich may, if desired, be further purified by fractional distillation.

The ethyl p-cyclohexyloxybenzoate may. be converted to the correspondingacid as follows: The ethyl ester obtained as above is refluxed withabout 200 ml. of 10 per cent sodium hydroxide for about one hour. Thesolution is then cooled and acidified with hydrochloric acid, whereuponpmyclohexyloxybenzoic acid precipitates. It is separated by filtrationand dried.

Dry cyclohexyloxybenzoic acid thus obtained from about 80 g. of ethylp-hydroxybenzoate weighed about '74 g. A portion of thep-cyclohexyloxybenzoic acid was prepared in analytically pure state byrecrystallizing it from glacial acetic acid. The purified acid melted atabout 186-188 C. Analysis showed the presence of about 70.7 per centcarbon and about 7.3 per cent hydrogen, as compared with the calculatedvalues of 70.9 per cent carbon and 7.3 per cent hydrogen.

Example 2 Example 1 is repeated except that in lace of loorontrifiuoride, about 12 ml. of concentrated sulfuric acid are added. Thereaction mixture is refluxed for about 2 hours. The ethylp-cyclohexyloxybenzoate is recovered by the method described inExample 1. The yield of p-cyclohexyloxybenzoic acid obtained is slightlyless than that obtained by the procedure described in Example 1.

Example 3 62 g. of ethyl p-hydroxybenzoate and 142 g. of cyclopentanolare dissolved in 150 ml. of benzene, and 21 ml. of concentrated sulfuricacid are added. The mixture is refluxed for 24 hours,

4 7 during which time 41 ml. of water are removed by means of aDean-Stark water trap. At the conclusion of the refluxing period thesolution is extracted with 15 per cent sodium hydroxide solution toremove any unreacted ethyl p-hydroxybenzoate. The benzene is evaporated,the residue of ethyl .p-cyclopentyloxybenzoate hydrolyzed and thep-cyclopentyloxybenzoic acid recovered by the procedure described inExample 1 for the corresponding cyclohexyl derivative.

The p-cyclopentyloxybenzoic acid when purified by recrystallization fromglacial acetic acid melted at about l79-180 C. Analysis showed thepresence of 69.74 percent carbon and 6.67 percent hydrogen, as comparedwith the calculated values of 69.88 percent carbon and 6.79 percenthydrogen. About 50 g. of purified pcyclopentyloxybenzoic acid wereobtained.

Example 4 p-Hydroxybenzoic acid was reacted with cyclopentene bysubstantially the same procedure as described in Example 1. The reactionmixture was washed with water and the benzene solution evaporated. Theresidue of p-cyclohexyloxyben zoic acid obtained by evaporating thebenzene solution was purified by recrystallization from glacial aceticacid. It melted at about 179- 180 0.

Example 5 The cyclopentyl and cyclohexyl ethers of other esters ofp-hydroxybenzoic acid are prepared in the same manner as the cyclopentylether of ethyl p-hydroxybenzoate. By using equivalent amounts ofmaterials, the directions disclosed in Examples 1, 2 and 3 areapplicable to the preparation of the ethers of these esters.

I claim:

1. In the process of preparing cycloalkyl ethers of p-hydroxybenzoylcompounds by reacting a cycloalkene with a p-hydroxybenzoyl compound,the step which comprises treating a mixture of a cycloalkene of thegroup consisting of cyclopentene and cyclohexene and a p-hydroxybenzoylcompound of the class consisting of phydroxybenzoic acid and lower alkylesters thereof with a catalyst of the class consisting of borontrifluoride and concentrated sulfuric acid at a temperature of fromabout 40 to about C.

2. The process of preparing cycloalkyl ethers of p-hydroxybenzoylcompounds which comprises heating to a temperature of from about 40 toabout 125 C. with a catalyst of the class of boron trifluoride andconcentrated sulfuric acid, a solution in an inert solvent of acycloalkene of the group consisting of cyclopentene and cyclohexene anda p-hydroxybenzoyl compound of the group consisting of p-hydroxybenzoicacid and lower alkyl esters thereof wherein the lower alkyl esterifyingradical has from 1 to 6 carbon atoms, and isolating the cycloalkyl etherof the p-hydroxybenzoyl compound produced in the reaction.

3. The process of preparing cycloalkyl ethers of p-hydroxybenzoylcompounds which comprises dissolving in an inert solvent one equivalentof a p-hydroxybenzoyl compound of the group consisting ofp-hydroxybenzoic acid and lower alkyl esters thereof wherein the alkylesterifying radical has from 1 to 6 carbon atoms, and about 2equivalents of a cycloalkene of the class consisting of cyclopentene andcyclohexene, adding about one half equivalent of a catalyst of the classconsisting of boron trifluoride and concentrated sulfuric acid, andheating the mixture to a temperature of from about 40 to about 125 0.,thereby causing the cycloalkene to react with the hydroxyl group of thep-hydroxybenzoyl compound, and isolating the cycloalkyl ether of thep-hydroxybenzoyl compound produced in the reaction.

4. A process according to claim 3 wherein the cycloalkene iscyclohexene.

5. A process according to claim 4 wherein the solvent is benzene.

6. The process of preparing ethyl p-cyclohexyloxybenzoate whichcomprises preparing in an inert solvent a solution of cyclohexene andethyl p-hydroxybenzoate, adding to the solution boron trifiuoride, andheating the solution to a temperature of from about 40 C. to about 1250, thereby causing the cyclohexene to react with the hydroxyl group ofthe ethyl p-hydroxybenzoate, and isolating the ethylp-cyclohexyloxybenzoate formed in the reaction.

7. In the process of preparing ethyl p-cyclohexyloxybenzoate by reactingcyclohexene with ethyl p-hydroxybenzoate, the step which comprisesreacting a mixture of cyclohexene and ethyl p-hydroxybenzoate in thepresence of boron trifiuoride and at a temperature of from about 40 toabout 125 0.

THOMAS P. CARNEY.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,070,848 Semon et a1 Feb. 16-;1937 2,128,901 Bass et al Sept. 6, 1938 2,128,975 Duzee et a1 Sept. 6,1938 2,439,818 McElvain et a1 Apr. 20, 1948

1. IN THE PROCESS OF PREPARING CYCLOALKYL ETHERS OF P-HYDROXYBENZOYLCOMPOUNDS BY REACTING A CYCLOALKENE WITH A P-HYDROXYBENZOYL COMPOUND,THE STEP WHICH COMPRISES TREATING A MIXTURE OF A CYCLOALKENE OF THEGROUP CONSISTING OF CYCLOPENTENE AND CYCLOHEXENE AND A P-HYDROXYBENZOYLCOMPOUND OF THE CLASS CONSISTING OF PHYDROXYBENZOIC ACID AND LOWER ALKYLESTERS THEREOF WITH A CATALYST OF THE CLASS CONSISTING OF BORONTRIFLUORIDE AND CONCENTRATED SULFURIC ACID AT A TEMPERATURE OF FROMABOUT 40* TO ABOUT 125* C.